Nephron最新文献

Background The cellular proteostasis machinery is essential for maintaining protein homeostasis by employing quality control systems that identify, sequester, and eliminate damaged or misfolded proteins. However, the accumulation of misfolded proteins can overwhelm these protective mechanisms, disrupting proteostasis. This phenomenon is a hallmark of numerous pathologies, including a variety of genetic disorders. In the secretory pathway, the buildup of misfolded proteins triggers endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR). The UPR serves as an adaptive mechanism, aiming to alleviate stress and restore cellular homeostasis. However, if ER stress is prolonged or severe, the UPR may fail to restore balance and apoptosis is induced. Summary This review introduces the intricate signaling pathways activated by the three UPR transmembrane sensors: protein-kinase R-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We briefly present the roles of the distinct transcriptional programs activated by each sensor in modulating the cellular response to protein stress and in determining cell fate. We discuss how genetic variants and environmental factors contribute to the heterogeneity observed in protein misfolding diseases. Finally, we critically evaluate select therapeutic strategies, specifically protein stabilization, trafficking modulation, and UPR sensor targeting approaches. Key message This review introduces the potential consequences of protein misfolding, which may not only impair protein function, but can also lead to toxic protein accumulation and stress induction. Using Fabry disease as a compelling example, we suggest that future therapeutic intervention may require nuanced, combination approaches that address both loss and gain of protein function.

Introduction Managing dialysis at home requires the involvement of the patient in decisions, treatment, and their illness and health. Evidence-based person-centered care interventions focus on listening to the patient's narrative, establishing a partnership between patients and healthcare professionals, and documenting care and treatment in a shared health plan. Therefore, a person-centered care intervention is expected to enhance the patient's ability to manage dialysis at home. This study aimed to identify and map evidence for person-centered interventions and home-based dialysis for individuals with kidney failure. Methods A scoping review was conducted based on the approach of Arksey and O'Malley. A systematic search was carried out in Medline, CINAHL, and Scopus for articles in all languages and without time restrictions. Person-centered care interventions concerning home dialysis were included. Two independent researchers assessed the literature. Data were extracted using NVIVO, and a relational analytical framework was employed to synthesise the data. Results The search identified 9,443 articles, of which 16 met the inclusion criteria. A total of 13 person-centered care interventions were identified. Eight interventions aimed to involve the patient in the decision regarding the type of dialysis modality, with six interventions identified to involve the patient in treatment, illness, and health. Only one intervention was identified to involve the patient in the decisions that follow once the patient has commenced dialysis treatment. Five interventions showed a correlation between a person-centered care intervention and the number of patients in home dialysis. Conclusion There is a need for interventions for patients in home dialysis to be adapted to a more person-centered care approach, particularly regarding the involvement of the patient in their treatment, illness and health, as well as the decisions that follow the initiation of dialysis treatment.

Introduction: In 2021, finerenone - a novel, selective non-steroidal mineralocorticoid receptor antagonist - was approved in the US to treat adults with CKD and T2D This study aimed to describe characteristics and short-term outcomes of patients prescribed finerenone since regulatory approval.

Methods: This was a retrospective cohort study using claims and electronic health records data from the OM1 Real-World Data Cloud™. A total of 15,948 US adults with a previous diagnosis of chronic kidney disease (CKD) and type 2 diabetes who initiated 10mg or 20mg finerenone between July 2021 and August 2023 were included. Dosing was evaluated at baseline and over up to 12-months' follow-up. Change from baseline in urine albumin-to-creatinine ratio (UACR) was evaluated at 4 and 12 months (among 913 and 443 patients, respectively, with available repeat UACR values). Hyperkalemia occurrence was determined at 12 months and over total follow-up.

Results: Median follow-up was 7.2 months. Mean age was 70.3 years; 44.1% were female. At baseline (-365; 0 days) 70% had CKD stage 3; for patients with UACR measurements 80.8% had moderate/severe albuminuria (≥30mg/g). Median UACR was 203mg/g. Co-medication use was: ACE inhibitors/ARBs (51%), SGLT2is (38%), and GLP-1 RAs (26%). 86% of patients initiated 10mg finerenone, and among 2212 patients still under observation at 12 months, 70% were on 10mg. For finerenone initiators with available UACR data, UACR was reduced by 33% at 4 months and 38% at 12 months. Hyperkalemia occurred in 1.2% of the cohort by 12 months (incidence 2.0 per 100 person-years).

Conclusion: Patients who initiated finerenone had a notable reduction in median UACR at 4 months, sustained at 12 months; hyperkalemia occurrence appeared to be low. These initial findings from US clinical practice should be complemented by results from other real-world cohorts of patients started on finerenone.

Introduction: The therapeutic efficacy of B cell-depleting anti-CD20 treatments is well established for children with steroid-sensitive nephrotic syndrome (SSNS), thus suggesting that B cells may play an important role in the occurrence of this disease. However, the role of B-cell survival factors and cytokines in SSNS has yet to be fully elucidated.

Methods: We used commercially available ELISA kits to determine the serum levels of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in 84 children with SSNS and 25 healthy controls. Then, we performed correlation analysis between these two serum factors and clinical parameters in children with SSNS.

Results: The serum level of BAFF in the relapse group was 1295.2 ± 584.2pg/ml, significantly higher than other groups (p<0.001). The serum level of APRIL in the relapse group was 2830.5 ± 945.8 pg/ml, significantly higher than the other groups (p<0.001). The proportion (%) of memory B cells was positively correlated with the levels of BAFF and APRIL in children with SSNS (Pearson's correlation coefficient: r=0.351, P=0.001; Pearson's r=0.234, P=0.032). The proportion (%) of transitional B cells was negatively correlated with the levels of BAFF (Pearson's r=-0.237, P=0.030) while the serum levels of IgG were negatively correlated with those of APRIL (Pearson's r=-0.274, P=0.012).

Conclusions: Our data indicate that BAFF appears to play a role in the recurrence of SSNS while APRIL appears to play a role in the pathogenesis of this condition, thus indicating that these molecules represent potential therapeutic targets for SSNS.

Fabry disease (FD) is a monogenic disease with highly variable clinical features. This variability suggests that additional pathogenetic pathways may exist besides the intra-lysosomal deposition of globotriaosylceramide (Gb3) and its deacylated form globotriaosylsphingosine (LysoGb3) caused by an enzyme deficiency. Research studies proved that the deposition of Gb3 and LysoGb3 can stimulate inflammatory processes. Mononuclear immune competent cells exposed to Gb3 deposition express adhesion molecules and release proinflammatory and fibrotic cytokines such as interleukin β, tumour necrosis factor-alpha (TNFα), and transforming growth factor beta (TGFβ). These processes determine the activation of inflammation processes associated with chronic inflammation and tissue fibrosis. The pathogenetic mechanisms stimulated by Gb3 and LysoGb3 deposition could become independent from the initial stimulus, causing an irreversible effect, in which Fabry disease-specific therapy can play a limited role. A new disease mechanism, "Agalopathy", would coexist with the enzyme deficiency. Missense variants in the coding sequence of the GLA gene would generate the misfolding of the altered protein alpha-galactosidase A. Emergence of misfolded proteins may generate stress of the endoplasmic reticulum (ER), leading to induction of the unfolded protein response (UPR). The UPR causes the release of proinflammatory cytokines and contributes to inflammatory status. This mechanism could be activated independently of glycolipid deposition, and its relationship with inflammatory pathways deserves more research. Strikingly, a zebrafish GLA knockout model that naturally lacks the enzyme that synthesizes Gb3 shows many alterations in lysosomal functions. These pieces of evidence suggest the involvement of alternative pathways independent of Gb3 in FD pathogenesis. This review aims to describe these processes' role in the pathogenesis of renal damage in FD or Agalopathy nephropathies.

Since the implementation of the Banff classification, the diagnosis and treatment of transplant rejection has been standardized. However, the rigid categorization of transplant pathology has limited our perspective on allograft inflammation, particularly disregarding those inflammatory infiltrates who do not reach the category of rejection. The term subclinical inflammation was introduced to designate the inflammation found in protocol biopsies, without significant renal function deterioration. Following the introduction of modern immunosuppression with tacrolimus and mycophenolate, subclinical rejection rate decreased, and less attention was paid to this entity. However, in the last decades several studies have evaluated the impact of lower levels of inflammation and demonstrated its negative consequences on long-term outcomes. Although, in some patients this subclinical inflammation is not permanent and can spontaneously disappear. The uncomplete definition of subclinical inflammation, which only considered renal function stability, and the evaluation of the biopsy as a definitive diagnosis, and not as a picture of an evolving process are the main reasons why managing this inflammation represents a challenge, especially when there is no pathogenic mechanism identified. In this review, we revise the "natural" history of inflammation in the kidney allograft and its possible origins based on cellular composition and transcriptomic expression changes in kidney biopsies. In addition, we propose an updated definition and an approach to manage it.

Glomerular diseases with organized deposits can be classified into various etiologies. A diagnostic algorithm based on clinical and pathological findings has been proposed. However, some cases cannot be diagnosed using existing algorithms. Here, we report the case of a 77-year-old man diagnosed with membranoproliferative glomerulonephritis (MPGN) with striated ultrastructural deposits, microfilament-like substructures with straight bands arranged in parallel in the subendothelial space by two sequential renal biopsies. His examinations and clinical findings were incompatible with known glomerular diseases with organized deposits. Dialysis was initiated 10 months after the second biopsy procedure. Furthermore, we report the first mass spectrometry analysis of laser micro-dissected glomeruli with striated ultrastructural deposits, which revealed significant levels of fibrinogen and fibronectin. Immunostaining was positive for fibrinogen, fibrin, and fibronectin in the subendothelial space. These findings suggest that the deposits were composed of a fibrin-fibronectin complex, and that accumulation of these fibrin-fibronectin complexes possibly induced endothelial injury, leading to MPGN. We also reviewed the literature on the clinical and pathological characteristics of the four cases with striated ultrastructural deposits. Our investigation showed that all patients had the MPGN pattern and striated ultrastructural deposits in the subendothelial space, and all underwent hemodialysis within 3 years after renal biopsy. Clinicians should be aware of the findings of glomerulonephritis with striated ultrastructural deposits since this disease may be a new entity and has a poor prognosis.  .

Background: Chronic kidney disease (CKD) elevates the risk of cardiovascular and overall mortality among maintenance hemodialysis (MHD) patients. Although initially designed to predict stroke in cases of atrial fibrillation, the CHA2DS2-VASc score demonstrates predictive utility, spanning several cardiovascular conditions. This study seeks to evaluate if the CHA2DS2-VASc score is effective in predicting cardiovascular and all-cause mortality for MHD patients.

Methods: The data are part of the "Prospective Study of the Prognosis of Patients on Chronic Hemodialysis" (PROHEMO) developed in Salvador, BA, Brazil. We grouped patients according to CHA2DS2-VASc score ≤2 (group 1) and >2 (group 2). Cox regression was used to estimate the hazard ratio of death (HR): unadjusted; and adjusted for hemoglobin, creatinine, albumin, phosphorus, PTH, liver disease, neoplasia/cancer, months of hemodialysis. Additionally, the distribution of each variable in the CHA2DS2-VASc score and its association with mortality were evaluated. Based on the observed associations and the distribution of age (with only 1.3% of patients aged >75 years) and hypertension (only 4.6% normotensive, leading to an imprecise association estimate), a modified CHA2DS2-VASc score was created.

Results: A total of 237 patients on hemodialysis (51.57 ± 12.46, 57% male) were included. Mean age was 51.6 ± 12.5 years. A total of 55 deaths, 21 from cardiovascular causes. Compared with CHA2DS2-VASc score <2, the unadjusted hazard of death (Model 1) for score ≥2 was twofold for all-cause mortality (HR=2.05; 95% CI: 1.20, 3.49) and more than three times higher for cardiovascular deaths (HR=3.53; 95% CI: 1.46, 8.54). These HRs did not change substantially with adjustment for covariates. In the most comprehensively adjusted Cox model, the HR for all-cause mortality was 2.43 (95% CI: 1.38, 4.23) and for cardiovascular mortality was 3.52 (95% CI: 1.40, 8.84). These results were similar to those observe for the modified version of CHA2DS2-VASc score.

Introduction: Everolimus (EVR)-induced kidney injury is rarely reported. Conversely, acute tubular necrosis (ATN) is a recognized complication of high-dose bisphosphonate therapy.

Case presentation: SM, a 69-year-old female patient with advanced breast cancer, developed severe kidney injury necessitating renal replacement therapy (RRT) shortly after initiating EVR treatment, while concurrently receiving chronic high-potency bisphosphonate therapy. Kidney biopsy confirmed ATN. Upon discontinuation of both EVR and bisphosphonates, her renal function gradually improved over several months, leading to the cessation of RRT. At a 2-year follow-up, her kidney function has returned to baseline.

Conclusion: In this case report, we outline the patient's clinical course and provide a pathophysiological rationale for the synergistic effect of EVR and bisphosphonates in promoting ATN. With the increasing use of EVR in various oncologic indications, we emphasize the reversible nature of this kidney injury and stress the importance of timely recognition and intervention.